The mortality has decreased from 50% to less than 20% as a result of early diagnosis, recognition of mild cases, and aggressive therapy. Death is usually due to cerebral edema or increased ICP, but it may be due to myocardial dysfunction, cardiovascular collapse, respiratory failure, renal failure, GI bleeding, status epilepticus, or sepsis. Patients who survive may have complete recovery, though neurologic impairment is common.

Parainfluenza, adenovirus, coxsackieviruses A and B, echovirus, Epstein-Barr virus, rubella virus, measles virus, cytomegalovirus, herpes simplex virus, parainfluenza viruses, and poliomyelitis viruses are less commonly involved than the pathogens listed above.

Abrupt onset of pernicious vomiting occurs 12 hours to 3 weeks after viral illness; the mean is 3 days. Neurologic symptoms usually occur 24-48 hours after onset of vomiting. Lethargy is usually the first neurologic manifestation.

Diarrhea and hyperventilation may be the first signs in children younger than 2 years. Irritability, restlessness, delirium, seizures, and coma occur.

Lovejoy initially described clinical stages I-V, Hurwitz modified to stages 0-5 to include a nonclinical stage (stage 0). The CDC uses the Hurwitz classification and adds stage 6. Stage 0 does not meet the CDC case definition because it does not meet the criteria for encephalopathy. The stages are as follows:

• Stage 0 - Alert, abnormal history and laboratory findings conversant with Reye syndrome, no clinical manifestations
• Stage 1 - Vomiting, sleepiness, and lethargy
• Stage 2 - Restlessness, irritability, combativeness, disorientation, delirium, tachycardia, hyperventilation, dilated pupils with sluggish response, hyperreflexia, positive Babinski sign, and appropriate response to noxious stimuli
• Stage 3 - Obtunded, comatose, decorticate rigidity, and inappropriate response to noxious stimuli
• Stage 4 - Deep coma, decerebrate rigidity, fixed and dilated pupils, loss of oculovestibular reflexes, and dysconjugate gaze with caloric stimulation
• Stage 5 - Seizures, flaccid paralysis, absent deep tendon reflexes (DTRs), no pupillary response, and respiratory arrest
• Stage 6 - Patients who cannot be classified because they have been treated with curare or other medication that alters level of consciousness

On liver function testing, ammonia levels are as much as 1.5 times normal (up to 1200 mcg/dL) 24-48 hours after the onset of mental status changes is the most frequent laboratory abnormality. Ammonia levels may return to the reference range in stages 4 and 5. Levels of transaminases, ALT, and AST increase to 3 times normal but may return to the reference ranges by stages 4 or 5. Bilirubin levels are >2 mg/dL (usually <3 mg/dL) in 10-15% of patients. If direct bilirubin is more than 15% of total. If the total is >3 mg/dL, consider other diagnoses. The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged >1.5-fold in >50% of patients.

Other labs: Lipase and amylase levels are elevated. Serum bicarbonate levels are decreased secondary to vomiting. BUN and creatinine levels are elevated. Expect hypoglycemia, particularly in children younger than 1 year. A serum glucose test is indicated for all children with altered mental status.

Head CT scanning may reveal cerebral edema, but the results are usually normal.

• Stages 0-1
  Keep the patient quiet. Frequently monitor vital signs and laboratory values.
  Correct fluid and electrolyte abnormalities, acidemia, and hypoglycemia. If the patient is initially hypoglycemic, administer dextrose 25% as an intravenous (IV) bolus at a dose of 1-2 mL/kg. If the initial pH is less than 7.2, consider the administration of bicarbonate (somewhat controversial) up to 1 mEq/ kg/h; avoid rapid correction or overcorrection. Maintain fluids, electrolytes, serum pH, albumin, serum osmolality, urine output, and glucose values. Overhydration may precipitate cerebral edema. Use colloids (e.g.: albumin) as necessary to maintain intravascular volume. Dehydration may compromise cardiovascular volume and reduce cerebral perfusion.
• Stage 2
  Continuous cardiorespiratory monitoring, placement of arterial lines and urine catheters to monitor urine output, and ECG and/or EEG are standard care.
  Correct hyperammonemia. The US Food and Drug Administration (FDA) has not approved any medication to treat hyperammonemia specifically due to Reye syndrome. Sodium phenylacetate/sodium benzoate (Ammonul), a medication that treats hyperammonemia is FDA approved for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. Use furosemide (Lasix) to control fluid overload, and administer insulin to maintain euglycemia. In addition, administer ondansetron (Zofran) 0.15 mg/kg (not to exceed 8 mg q8h) during the first 15 minutes of the initial dose. If the ammonia level is more than 500 mcg/dL or if the patient's condition fails to respond to the initial dose of sodium phenylacetate/sodium benzoate, start dialysis, preferably hemodialysis. Prevent increased ICP. Elevate the head of the bed and avoid overhydration and use of hypo-osmotic fluids.
• Stages 3-5
  Continuously monitor ICP (intracranial pressure), central venous pressure, arterial pressure, and/or end-tidal carbon dioxide. Manage the airway with rapid-sequence intubation and ventilation as appropriate for raised ICP. Treat increased ICP by following standard guidelines. Treat seizures with phenytoin 10-20 mg/kg IV as a loading dose followed by 5 mg/kg/d IV divided every 6 hours or fosphenytoin dosed as 10-20 mg/kg phenytoin equivalents (PEs).
  Correct coagulopathy (PT >16 seconds), particularly if an intracranial bolt and/or liver biopsy is required. In rare cases, an exchange transfusion is required.